Abstract
The endometrium is a complex, steroid-dependent tissue that undergoes dynamic cyclical remodelling. Transformation of stromal fibroblasts (ESC) into specialised secretory cells (decidualization) is fundamental to the establishment of a receptive endometrial microenvironment which can support and maintain pregnancy. Androgen receptors (AR) are present in ESC; in other tissues local metabolism of ovarian and adrenal-derived androgens regulate AR-dependent gene expression. We hypothesised that altered expression/activity of androgen biosynthetic enzymes would regulate tissue availability of bioactive androgens and the process of decidualization. Primary human ESC were treated in vitro for 1–8 days with progesterone and cAMP (decidualized) in the presence or absence of the AR antagonist flutamide. Time and treatment-dependent changes in genes essential for a) intra-tissue biosynthesis of androgens (5α-reductase/SRD5A1, aldo-keto reductase family 1 member C3/AKR1C3), b) establishment of endometrial decidualization (IGFBP1, prolactin) and c) endometrial receptivity (SPP1, MAOA, EDNRB) were measured. Decidualization of ESC resulted in significant time-dependent changes in expression of AKR1C3 and SRD5A1 and secretion of T/DHT. Addition of flutamide significantly reduced secretion of IGFBP1 and prolactin and altered the expression of endometrial receptivity markers. Intracrine biosynthesis of endometrial androgens during decidualization may play a key role in endometrial receptivity and offer a novel target for fertility treatment.
Highlights
With a mid-cycle peak in concentrations of the AR agonist testosterone (T) at the time of ovulation[7]
DHEA is converted to androstenedione (A4) by the action of the enzyme 3-β -hydroxysteroid dehydrogenase (3β HSD) which we have previously reported is expressed in decidualized endometrium and in isolated ESC2
Additional evidence from studies comparing the behaviour of human ESC decidualized with progesterone plus cyclic adenosine monophosphate (cAMP) combined with the addition of exogenous DHT have reported that regulation of prolactin secretion, morphological transformation of ESC and resistance to oxidative stress are augmented by androgen action[15,16,17]
Summary
With a mid-cycle peak in concentrations of the AR agonist testosterone (T) at the time of ovulation[7]. Primary stromal cells isolated from human endometrium (ESC) can be stimulated to undergo a robust decidualization response by the addition of progesterone and the second messenger molecule cyclic adenosine monophosphate (cAMP)[11] This in vitro decidualization phenocopies the post-ovulatory differentiation of ESC during a fertile cycle with characteristic changes in cellular morphology[11] and increased secretion of proteins such as insulin-like growth factor-binding protein 1 (IGFBP1)[12] and prolactin[13]. Female mice lacking a functional Ar have altered neuroendocrine signalling and ovarian function and are subfertile[20]; studies using ovarian transplantation suggest Ar plays a key role in uterine development[21] Taken together, these data are consistent with the uterus being an androgen target tissue and that AR-dependent signalling is essential for the regulation of uterine function. Our novel data demonstrate that intracrine androgens can complement the effects of progesterone by acting to enhance the decidualization response and support an optimal environment for successful establishment of pregnancy
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
